What children know about alcohol and how they know it.
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Biomedical subjects
P Silva
Publications and source records attributed to P Silva.
Neural control of shark rectal gland.
Veratrum alkaloids stimulated salt secretion by the isolated perfused rectal gland of Squalus acanthias. Stimulation by veratrine was prevented by the nerve channel blockers tetrodotoxin and procaine and was not evident in a preparation of dispersed rectal gland cells. Vasoactive intestinal peptide (VIP)-like immunoreactivity was detected by histological techniques in neuronal tissue within the rectal gland. Veratrine stimulation caused the release of immunoreactive VIP into the venous effluent of perfused glands. The stimulatory action of veratrine was inhibited by somatostatin, another neuropeptide known to be present in nerves of Squalus rectal gland. These findings suggest the likelihood of neural modulation of rectal gland function.
Adenosine↗
Characterization of ANP receptors in rabbit inner medullary collecting duct cells.
The final urinary Na+ concentration is determined in the inner medullary collecting duct (IMCD) and is under hormonal control. In suspensions of IMCD cells we have previously shown that atrial natriuretic peptide (ANP) inhibits Na+ transport-dependent O2 consumption and causes an increase in cellular guanosine 3',5'-cyclic monophosphate (cGMP) content. In this study we sought to identify and characterize the receptor for ANP in these cells. Equilibrium binding studies revealed a single class of cell surface ANP receptors of high affinity (Kd = 66.2 pM) with a total number of 3,000 sites/cell. Specificity of these receptors was shown by the rank order of binding affinities for ANP analogues: ANP-(1-28) = ANP-(4-28) greater than ANP-(5-28) much greater than ANP-(5-25). We have further defined this receptor in a solubilized cell preparation and found it to be of molecular mass 130 kDa by affinity cross linking and sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis. This is the first characterization of an epithelial cell receptor for ANP; as in other systems this receptor appears to be linked to transport processes via the production of cGMP.
Animals↗
Atrial natriuretic peptides inhibit conductive sodium uptake by rabbit inner medullary collecting duct cells.
The inner medullary collecting duct (IMCD) effects net sodium reabsorption under the control of volume regulatory hormones, including atrial natriuretic peptides (ANP). These studies examined the mechanisms of sodium transport and its regulation by ANP in fresh suspensions of IMCD cells. Sodium uptake was inhibited by amiloride but insensitive to furosemide, bu-metanide, and hydrochlorthiazide. These results are consistent with uptake mediated by a sodium channel or Na+/H+ exchange. To determine the role of sodium channels, cells were hyperpolarized by preincubation in high potassium medium followed by dilution into potassium-free medium. Membrane potential measurements using the cyanine dye, Di(S)-C3-5 verified a striking hyperpolarization of IMCD cells using this protocol. Hyperpolarization increased the apparent initial rate of sodium uptake fourfold. Amiloride and ANP inhibited potential-stimulated sodium uptake 73% and 65%, respectively; the two agents together were not additive. Addition of 5 mM sodium to hyperpolarized cells resulted in a significant amiloride-sensitive depolarization. Half-maximal inhibition of potential-driven sodium uptake occurred at 3 X 10(-7) M amiloride, and 5 X 10(-11) M ANP. We conclude that sodium enters IMCD cells via a conductive, amiloride-sensitive sodium channel, which is regulated by ANP. ANP inhibition of luminal sodium entry in the IMCD appears to contribute to the marked natriuretic effect of this hormone in vivo.
Amiloride↗
Alcohol knowledge and experience in children aged 9 and 11.
An interview study of New Zealand children initially aged 9 (n = 743) and at the second interview aged 11 (n = 795) investigated the children's knowledge and experience of alcohol. The majority had tried alcohol and, by age 11, over 40% had at least a sip or drink in a typical month. There were indications of a shift towards a more adult drinking pattern in that more children at age 11 drank from their own glass but no increase in the proportion of those with experience of drinking from age 9 to 11. For the majority of children the context of use at both age 9 and age 11 was a parental one. Most children described the effects of drinking alcohol and the characteristics of drunkenness in somewhat negative terms. Television was nominated as a source of knowledge in this area by 37% of the children at age 9 and 47% of the children at age 11.
Alcohol Drinking↗
Dibutyryl cyclic AMP inhibits transport dependent QO2 in cells isolated from the rabbit medullary ascending limb.
Because the medullary thick ascending limb of the loop of Henle is the target of several polypeptide hormones that stimulate adenyl cyclase in this nephron segment, we examined the effects of cyclic AMP on thick ascending limb of the loop of Henle cells isolated by enzymatic digestion and density gradient centrifugation from the outer medulla of the rabbit kidney. The functional parameter that was measured was transport dependent oxygen consumption. Oxygen consumption was measured using a polarographic oxygen electrode in a constant temperature chamber. We found that dibutyryl cyclic AMP inhibited oxygen consumption in a dose dependent way. Maximal inhibition was observed at a concentration of 10(-5) M. The effect of dibutyryl cyclic AMP was not present in the absence of either sodium, chloride or both implying that its effect is restricted to the sodium and chloride dependent oxygen consumption. The effect of dibutyryl cyclic AMP was additive to that of furosemide 10(-4) M while that of furosemide was not additive to that of cyclic AMP suggesting that the site of action of cyclic AMP is distal to that of furosemide. The effect of dibutyryl cyclic AMP was not additive to that of ouabain and was absent in cells where oxygen consumption was stimulated with amphotericin B in the absence of chloride indicating that it has no effect on Na-K-ATPase.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Physiological and clinical implications of medullary hypoxia.
Because of countercurrent capillary flow, the renal medulla of mammalian kidneys is perpetually hypoxic, the ambient oxygen tension hovering close to the critical Po2 that limits respiration. Within this environment, the mitochondria-rich cells of the medullary thick ascending limb (mTAL) require large amounts of energy to accomplish the work of ion transport. These cells are therefore uniquely vulnerable to anoxic damage, as is demonstrated by morphological changes in isolated perfused rat kidneys. The lesions of hypoxia in mTAL cells of perfused kidneys can be greatly exaggerated by maneuvers that increase the work of transport and practically eliminated by inhibitors of active transport, like ouabain or furosemide, or by interrupting glomerular filtration. The close dependence of experimental ischemic injury on active transport suggests that endogenous inhibitors of transport may play an important physiological role in modulating the susceptibility of the medulla to anoxic injury in health and disease. Candidates for this role include adenosine and locally formed derivatives of arachidonic acid that have been shown to influence metabolism and transport.
Acute Kidney Injury↗
Atrial natriuretic peptide stimulates salt secretion by shark rectal gland by releasing VIP.
Salt secretion by the isolated perfused rectal gland of the spiny dogfish shark, Squalus acanthias, is stimulated by synthetic rat atrial natriuretic peptide (ANP II) as well as extracts of shark heart, but not by 8-bromo-cyclic guanosine 5'-monophosphate. Cardiac peptides have no effect on isolated rectal gland cells or perfused tubules, suggesting that stimulation requires an intact gland. The stimulation of secretion by ANP II is eliminated by maneuvers that block neurotransmitter release. These include: perfusion with procaine (10(-2) M), perfusion with high Mg2+ (9.5 mM) and low Ca2+ (0.5 mM) concentrations, and addition to the perfusate of the calcium channel blockers nifedipine (10(-6)M), diltiazem (5 X 10(-5)M), or verapamil (10(-4)M). Cardiac peptides stimulate the release of vasoactive intestinal peptide (VIP), known to be present in rectal gland nerves, into the venous effluent or perfused glands in parallel with their stimulation of salt secretion, but the release of VIP induced by ANP II is prevented by perfusion with procaine. Cardiac peptides thus appear to regulate rectal gland secretion by releasing VIP from neural stores within the gland. It is possible that other physiological effects of these hormones might be explained by an action to enhance local release of neurotransmitters.
Adenosine↗
cGMP mediates effects of atrial peptides on medullary collecting duct cells.
Atrial natriuretic peptides (ANP) stimulate renal Na+ excretion by poorly understood mechanisms, possibly involving direct inhibition of Na+ transport in the renal medulla. We have previously shown that human ANP 4-28 (hANP) inhibits Na+ entry-dependent O2 consumption (QO2) in rabbit inner medullary collecting duct (IMCD) cells. Because ANP actions in other tissues appear to be mediated by guanosine 3',5'-cyclic monophosphate (cGMP), the present studies examined the role of cyclic nucleotides in IMCD cell responses to ANP. 8-Bromo-cGMP (8-BrcGMP) diminished QO2 by 23.5 +/- 1.2% (SE) in IMCD cells but had no effect in cells derived from outer medullary collecting duct (OMCD); dibutyryl-adenosine 3',5'-cyclic monophosphate (cAMP) was without effect in IMCD cells. The inhibitory effect of BrcGMP was not additive with ANP, amiloride, or ouabain. Amphotericin, which enhances Na+ entry into cells, prevented the inhibitory effect of 8-BrcGMP. These results indicate that 8-BrcGMP, like ANP, inhibited Na+ entry in IMCD cells. hANP stimulated a 10-fold increase in cGMP in IMCD cells without altering IMCD cAMP levels or OMCD cGMP levels. Isobutyl methylxanthine, which inhibits phosphodiesterase activity, enhanced both cGMP accumulation and inhibition of QO2 by submaximal levels (10(-9) M) of ANP. Nitroprusside raised cGMP levels in both IMCD and OMCD cells but inhibited QO2 only in IMCD cells. We conclude that cGMP mediates the transport effects of ANP in IMCD cells. Our results indicate that cGMP may play an important role in the regulation of sodium transport in renal epithelia.
1-Methyl-3-isobutylxanthine↗
Role of alpha-adrenergic hormones in potassium homeostasis in the rat.
To determine whether alpha-adrenergic stimulation impairs extrarenal potassium disposal in the rat, we studied the effect of an alpha-agonist and antagonist on the rise in plasma potassium concentration produced by a potassium infusion of 3 mEq KCl/kg over a 90-minute period to nephrectomized rats. Compared with KCl alone, the alpha-agonist phenylephrine caused more than a 25% increment in the peak plasma potassium, and reduced the volume of distribution of the potassium load. Addition of the alpha-blocker, phentolamine, to phenylephrine completely abolished the increment in potassium caused by KCl infusion. There were no differences in plasma bicarbonate, arterial pH, or plasma glucose levels among the groups. When an identical protocol was performed in nephrectomized rats also prepared by adrenalectomy, induction of diabetes, and chemical sympathectomy, the rise in plasma potassium level after KCl infusion was again augmented by phenylephrine. Addition of phentolamine also markedly blunted the increment in potassium in this group. These results show that alpha-adrenergics impair extrarenal potassium disposal in the rat. The effect does not depend on endogenous insulin or other potassium-regulatory factors. alpha-Adrenergics appear to play an important role in extrarenal potassium homeostasis.
Adrenalectomy↗
Renal fuel utilization, energy requirements, and function.
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Energy Metabolism↗
Mitochondrial activity: a possible determinant of anoxic injury in renal medulla.
In brain, heart and kidney, cell work in the absence of oxygen has been thought to precipitate anoxic damage by increasing the rate of depletion of cellular energy stores. In the medullary thick ascending limb of isolated perfused rat kidneys, however, reduction of ATP synthesis by a variety of mitochondrial or metabolic inhibitors caused ATP depletion comparable to that produced by oxygen deprivation but did not reproduce the lesions of anoxia. In these cells, unrestrained mitochondrial activity may be an important source of anoxic injury.
Adenosine Triphosphate↗
Inhibition of chloride secretion by BaCl2 in the rectal gland of the spiny dogfish, Squalus acanthias.
In the rectal gland of the spiny dogfish (Squalus acanthias), chloride enters the cell via a cotransport system together with sodium and potassium in a 2 Cl-: 1 Na+: 1 K+ stoichiometry. The system is energized by the electrochemical potential for sodium directed into the cell. Sodium is extruded from the cell by Na-K-ATPase located on the basolateral cell membrane. Chloride leaks into the lumen following a favorable electrical gradient. Potassium is thought to recirculate across the basolateral cell membrane. Since barium ions inhibit the efflux of potassium from cells we used barium chloride to explore the role of potassium in the process of stimulated secretion of chloride by the gland. The secretion of chloride was stimulated with theophylline 2.5 X 10(-4)M and dibutyryl cyclic AMP 5 X 10(-5)M. Ba++ inhibited the secretion of chloride in a way that was reversible and dose dependent. The reduction in secretion was associated with a parallel fall in transglandular electrical potential. Inhibition was half maximal at a concentration of Ba++ of 10(-3)M. The reduction in efflux of potassium produced by Ba++ presumably decreases the potassium diffusion potential, thus reducing the electronegativity of the cell and dissipating the driving force for chloride across the apical cell membrane. Recirculation of K+ across the basolateral border of the cell would thus be essential for the maintenance of chloride secretion by the gland.
Animals↗
Cyclic AMP-dependent stimulation of Na,K-ATPase in shark rectal gland.
Scatchard analysis of 3H ouabain bound to isolated rectal gland cells as a function of increasing ouabain concentrations produced a concave curvilinear plot that was resolved into two specific sites with either a high (I) or low (II) affinity for ouabain. Cyclic cAMP/theophylline (+/- furosemide, 10(-4) M) increased the amount of 3H ouabain bound to the high-affinity site I. Vanadate, a phosphate congener which promotes formation of the ouabain-binding state of the enzyme, mimicked the effects of cAMP/theophylline at low concentrations of ouabain, suggesting that cAMP/theophylline increases binding to site I by enhancing the rate of turnover of resident enzyme. Enhanced 86Rb uptake seen following cAMP/theophylline administration was primarily associated with increased flux through the high-affinity ouabain site, and this stimulation was not obliterated by the co-administration of furosemide. A model was presented which suggested the presence of two noninteracting pools of enzyme or isozymes which exhibit either a high or low affinity for ouabain. Cyclic AMP both stimulated turnover via site I, and modified the kinetics of binding of 3H ouabain to site II. The (ave) Kd of 3H ouabain for site II was increased from 3.6 microM (controls) to 0.5 microM (cAMP/theophylline) and the Hill coefficient was modified from 0.45 (controls) to 1.12 (cAMP/theophylline), suggesting a transition from a negative- to a noncooperative binding state. While furosemide reversed the effects of cAMP/theophylline on site II kinetics, it did not obliterate cAMP/theophylline effects on site I. This suggests that cAMP may alter the intrinsic turnover rate of this particular pool of Na,K-ATPase in shark rectal gland.
Animals↗
Differential responsiveness of proximal tubule segments to metabolic inhibitors in the isolated perfused rat kidney.
Rat kidneys were perfused for 90 minutes with cyanide, rotenone, antimycin, 2-deoxyglucose, or combinations of rotenone or antimycin with 2-deoxyglucose in oxygenated Krebs-albumin medium. Following perfusion, proximal tubule injury was evaluated by light microscopy. The types of lesions seen were similar to those previously reported after hypoxic perfusion and included brush border clubbing/mitochondrial swelling in S1 and S2 and cytoplasmic edema or cell fragmentation in S3. This finding supports the contention that these lesions represent characteristic responses of these segment types and that the S3 response differs from that in S1 and S2. S1 appeared most vulnerable to low dose cyanide or inhibition of mitochondrial electron transport (rotenone, antimycin). Inhibition of glycolysis (2-deoxyglucose) only produced injury in S2 tubules. With high dose cyanide or a combination of 2-deoxyglucose with either rotenone or antimycin, there was diffuse proximal tubule damage. Thus S3 appeared more resistant than the convoluted tubular segments to both inhibition of glycolysis and to inhibition of mitochondrial electron transport. This finding stands in contrast to the selective vulnerability of the S3 segment in ischemic renal injury.
Animals↗
Hypoxic injury in the proximal tubule of the isolated perfused rat kidney.
The effect of hypoxia on the morphology of the proximal tubule was examined in isolated rat kidneys perfused with Krebs-albumin medium, gassed with 95% N2/5% CO2 for 45, 90 and 190 min. The major findings were heterogeneity of types of cell injury and definable topographical zones of protection from damage. The characteristic injury in S1 and S2 was that of mitochondrial swelling and brush border alterations that progressed to complete disorganization of this zone. S3 manifested two distinct lesions, one characterized by cell swelling and the other by tubular epithelial fragmentation. Protection from these injuries was seen in tubules located in periarterial zones, apparently due to gradients of oxygenation. The same types of injury but without zones of protection were seen after perfusion with cyanide (10 mM) in oxygenated medium. A "reflow" period of oxygenated perfusion did not alter the fundamental character of these lesions but affected tubules showed progression of damage while there was preservation of tubules in periarterial areas. Thus the responses of the proximal tubule to hypoxic injury depends both on segment type (S1, S2 versus S3) and on tubular location in relation to O2 availability. Additional factors appear to determine the type of response in S3 tubules.
Animals↗
Transport-dependent cell injury in the S3 segment of the proximal tubule.
Two distinct types of injury, cytoplasmic edema and cell fragmentation occur in the S3 segment of the proximal tubule in isolated hypoxic perfused rat kidneys (Krebs-albumin medium gassed without O2). The proportion of S3 tubules with fragmentation strongly correlated with the GFR and urine output during the perfusion, and approached 100% when the GFR was increased by high perfusion pressure. Conversely, the fragmentation lesion was absent and the edema lesion extensive when tubular transport was inhibited by perfusion with hyperoncotic medium to prevent glomerular filtration or by addition of ouabain (10(-2) M) to the perfusate. Polyene antibiotics increase membrane permeability and thus the work of active electrolyte transport. Perfusion with amphotericin (3 X 10(-5) M) or nystatin (200 U/mliter) in oxygenated medium also produced fragmentation in S3. The lesion was prevented in the non-filtering kidney. Ouabain completely eliminated the cell fragmentation due to nystatin and significantly reduced that due to amphotericin. These results suggest that the injury of cell fragmentation is enhanced by transport activity and diminished when transport is inhibited. The edema lesion appears fundamentally different and more akin to lesions described in ischemia where tubular flow is absent, active transport is diminished, and the morphologic changes appear related to loss of cell volume regulation. The type of hypoxic damage exhibited by proximal tubular S3 segments may therefore be conditioned by active ion transport of tubular cells.
Amphotericin B↗
Glucose metabolism in renal tubular function.
Heterogeneity of metabolic activity along the nephron points to a very varied relationship between glucose metabolism and ion transport. Glycolysis is linked closely to free-water clearance and possibly to sodium, potassium, and hydrogen ion transport. Glucose oxidation, while not the major source of renal energy, is crucial in sodium, potassium, and phosphate reabsorption. Gluconeogenesis recovers carbon compounds generated during the process of renal ammoniagenesis. Glucose synthesis and active sodium transport appear to compete for renal ATP, although no regulatory function for this competition has been identified. Glucose formed in the proximal tubule may support free-water clearance in adjacent distal tubule, but is not thought to contribute to any medullary function. The complex network of biosynthetic and catabolic pathways of glucose metabolism may have evolved in the kidney to protect the organism against wide variations in glucose demand which would otherwise be unavoidable during the course of rapidly fluctuating renal electrolyte loads.
Animals↗